This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We propose to investigate if the nuclear DNA from a patient's egg, carrying mitochondrial (mt)DNA mutations in the cytoplasm, transplanted into an enucleated egg donated by a healthy donor, thereby replacing the mitochondrial defect with healthy mtDNA but retaining the patient's nuclear genome. Next, we will examine the developmental competence of reconstructed eggs by assessing fertilization, in vitro embryo development and isolation of embryonic stem (ES) cells. It is highly likely that results generated in this proposal will provide a reliable, new approach for genetic intervention in the case of mitochondrial diseases and improve the chances of a mother with mtDNA mutation having a healthy, asymptomatic child. Our recent studies demonstrate the feasibility and efficacy of this approach in the rhesus monkey. We showed that reconstructed oocytes produced after chromosome transfer are nearly homoplasmic, capable of supporting normal fertilization and competent for full term development. These studies are performed within the facilities of the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics &Gynecology, OHSU.